Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0EJBM4)

• DOT Name: Melatonin-related receptor (GPR50)
• Synonyms: G protein-coupled receptor 50; H9
• Gene Name: GPR50
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Androgen insensitivity syndrome
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Episodic kinesigenic dyskinesia 1
  Major depressive disorder
  Mental disorder
  Neoplasm
  Obesity
  Schizophrenia
  Seasonal affective disorder
  Autism spectrum disorder
  Bipolar disorder
  Depression
• UniProt ID: MTR1L_HUMAN
• Pfam ID: PF00001
• Sequence:
  MGPTLAVPTPYGCIGCKLPQPEYPPALIIFMFCAMVITIVVDLIGNSMVILAVTKNKKLR
  NSGNIFVVSLSVADMLVAIYPYPLMLHAMSIGGWDLSQLQCQMVGFITGLSVVGSIFNIV
  AIAINRYCYICHSLQYERIFSVRNTCIYLVITWIMTVLAVLPNMYIGTIEYDPRTYTCIF
  NYLNNPVFTVTIVCIHFVLPLLIVGFCYVRIWTKVLAARDPAGQNPDNQLAEVRNFLTMF
  VIFLLFAVCWCPINVLTVLVAVSPKEMAGKIPNWLYLAAYFIAYFNSCLNAVIYGLLNEN
  FRREYWTIFHAMRHPIIFFSGLISDIREMQEARTLARARAHARDQAREQDRAHACPAVEE
  TPMNVRNVPLPGDAAAGHPDRASGHPKPHSRSSSAYRKSASTHHKSVFSHSKAASGHLKP
  VSGHSKPASGHPKSATVYPKPASVHFKADSVHFKGDSVHFKPDSVHFKPASSNPKPITGH
  HVSAGSHSKSAFSAATSHPKPTTGHIKPATSHAEPTTADYPKPATTSHPKPTAADNPELS
  ASHCPEIPAIAHPVSDDSDLPESASSPAAGPTKPAASQLESDTIADLPDPTVVTTSTNDY
  HDVVVIDVEDDPDEMAV
• Function: G protein-coupled receptor that plays a role in numerous physiological processes including regulation of energy metabolism, neurite outgrowth or cell migration. Promotes self-renewal and neuronal differentiation of neural progenitor cells through activation of the NOTCH and WNT/beta-catenin signaling pathways. Modulates the KAT5-dependent glucocorticoid receptor signaling by modulating KAT5 subcellular compartmentalisation. Plays also a role in the activation TGFBR1 in the absence of TGFBR2 by interfering with FKBP1A binding to TGFBR1, leading to induction of both canonical and non-canonical SMAD signaling pathways resulting in inhibition of proliferation or promotion of migration ; [C-terminal domain]: Upon cleavage by CAPN1, functions as a scaffold in the nucleus for interacting partners such as GTF2I to promote FOS promoter activation.
• Tissue Specificity: Hypothalamus and pituitary.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Posttranslational Modification	[2]
Androgen insensitivity syndrome	DISUZBBO	Strong	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[6]
Mental disorder	DIS3J5R8	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Obesity	DIS47Y1K	Strong	Genetic Variation	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Seasonal affective disorder	DIS908VO	Strong	Genetic Variation	[10]
Autism spectrum disorder	DISXK8NV	moderate	Biomarker	[11]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[12]
Depression	DIS3XJ69	Limited	Genetic Variation	[7]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Melatonin-related receptor (GPR50).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Melatonin-related receptor (GPR50).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Melatonin-related receptor (GPR50).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Melatonin-related receptor (GPR50).	[16]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Melatonin-related receptor (GPR50).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Melatonin-related receptor (GPR50).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Melatonin-related receptor (GPR50).	[19]

References

• [1] The orphan GPR50 receptor promotes constitutive TGF receptor signaling and protects against cancer development.Nat Commun. 2018 Mar 23;9(1):1216. doi: 10.1038/s41467-018-03609-x.
• [2] Significant association between GPR50 hypomethylation and AD in males.Mol Med Rep. 2019 Aug;20(2):1085-1092. doi: 10.3892/mmr.2019.10366. Epub 2019 Jun 6.
• [3] Evaluation of GPR50, hMel-1B, and ROR-alpha melatonin-related receptors and the etiology of adolescent idiopathic scoliosis.J Pediatr Orthop. 2010 Sep;30(6):539-43. doi: 10.1097/BPO.0b013e3181e7902c.
• [4] Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders.J Pineal Res. 2011 Nov;51(4):394-9. doi: 10.1111/j.1600-079X.2011.00902.x. Epub 2011 May 26.
• [5] Physiological crosstalk between the AC/PKA and PLC/PKC pathways modulates melatonin-mediated, monochromatic-light-induced proliferation of T-lymphocytes in chickens.Cell Tissue Res. 2017 Sep;369(3):555-565. doi: 10.1007/s00441-017-2644-6. Epub 2017 Jun 28.
• [6] GPR50 is not associated with childhood-onset mood disorders in a large sample of Hungarian families.Psychiatr Genet. 2007 Dec;17(6):347-50. doi: 10.1097/YPG.0b013e3281ac232f.
• [7] Involvement of GPR50 polymorphisms in depression: independent replication in a prospective elderly cohort.Brain Behav. 2015 Mar;5(3):e00313. doi: 10.1002/brb3.313. Epub 2015 Feb 8.
• [8] Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels.J Lipid Res. 2006 Apr;47(4):761-6. doi: 10.1194/jlr.M500338-JLR200. Epub 2006 Jan 25.
• [9] Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor.Mol Psychiatry. 2005 May;10(5):470-8. doi: 10.1038/sj.mp.4001593.
• [10] Association of the intronic rs2072621 polymorphism of the X-linked GPR50 gene with affective disorder with seasonal pattern.Eur Psychiatry. 2012 Jul;27(5):369-71. doi: 10.1016/j.eurpsy.2011.02.011. Epub 2011 May 11.
• [11] Mutation screening of melatonin-related genes in patients with autism spectrum disorders.BMC Med Genomics. 2010 Apr 8;3:10. doi: 10.1186/1755-8794-3-10.
• [12] Association of GPR50, an X-linked orphan G protein-coupled receptor, and affective disorder in an independent sample of the Scottish population.Neurosci Lett. 2010 May 21;475(3):169-73. doi: 10.1016/j.neulet.2010.03.072. Epub 2010 Apr 3.
• [13] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [14] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.